title: Acid ceramidase promotes nuclear export of PTEN through sphingosine 1-phosphate mediated Akt signaling.
abstract: The tumor suppressor PTEN is now understood to regulate cellular processes at the cytoplasmic membrane, where it classically regulates PI3K signaling, as well as in the nucleus where multiple roles in controlling cell cycle and genome stability have been elucidated. Mechanisms that dictate nuclear import and, less extensively, nuclear export of PTEN have been described, however the relevance of these processes in disease states, particularly cancer, remain largely unknown. We investigated the impact of acid ceramidase on the nuclear-cytoplasmic trafficking of PTEN. Immunohistochemical analysis of a human prostate tissue microarray revealed that nuclear PTEN was lost in patients whose tumors had elevated acid ceramidase. We found that acid ceramidase promotes a reduction in nuclear PTEN that is dependent upon sphingosine 1-phosphate-mediated activation of Akt. We were further able to show that sphingosine 1-phosphate promotes formation of a complex between Crm1 and PTEN, and that leptomycin B prevents acid ceramidase and sphingosine 1-phosphate mediated loss of nuclear PTEN, suggesting an active exportin-mediated event. To investigate whether the tumor promoting aspects of acid ceramidase in prostate cancer depend upon its ability to export PTEN from the nucleus, we used enforced nuclear expression of PTEN to study docetaxel-induced apoptosis and cell killing, proliferation, and xenoengraftment. Interestingly, while acid ceramidase was able to protect cells expressing wild type PTEN from docetaxel, promote proliferation and xenoengraftment, acid ceramidase had no impact in cells expressing PTEN-NLS. These findings suggest that acid ceramidase, through sphingosine 1-phosphate, promotes nuclear export of PTEN as a means of promoting tumor formation, cell proliferation, and resistance to therapy.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Beckham
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Cheng
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.forename: S Tucker
authors.initials: ST
authors.lastname: Marrison
authors.forename: James S
authors.initials: JS
authors.lastname: Norris
authors.forename: Xiang
authors.initials: X
authors.lastname: Liu
mesh_terms: D055573:Acid Ceramidase / Q000235:genetics / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology; D000097606:Exportin 1 Protein
chemical_list: D055573:Acid Ceramidase; D000970:Antineoplastic Agents; D000077143:Docetaxel; D028884:Karyopherins; D008246:Lysophospholipids; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018160:Receptors, Cytoplasmic and Nuclear; D013110:Sphingosine; D043823:Taxoids; D000097606:Exportin 1 Protein; C060506:sphingosine 1-phosphate; C494929:PTEN protein, human; C526693:ASAH1 protein, human